RNA viruses generate defective viral genomes (DVGs) that can interfere with replication of the parental wild-type virus. To examine their therapeutic potential, we created a DVG by deleting the capsid-coding region of poliovirus. Strikingly, intraperitoneal or intranasal administration of this genome, which we termed eTIP1, elicits an antiviral response, inhibits replication, and protects mice from several RNA viruses, including enteroviruses, influenza, and SARS-CoV-2. While eTIP1 replication following intranasal administration is limited to the nasal cavity, its antiviral action extends non-cell-autonomously to the lungs. eTIP1 broad-spectrum antiviral effects are mediated by both local and distal type I interferon responses. Importantly, while a single eTIP1 dose protects animals from SARS-CoV-2 infection, it also stimulates production of SARS-CoV-2 neutralizing antibodies that afford long-lasting protection from SARS-CoV-2 reinfection. Thus, eTIP1 is a safe and effective broad-spectrum antiviral generating short- and long-term protection against SARS-CoV-2 and other respiratory infections in animal models.

RNA 病毒会产生有缺陷的病毒基因组 (DVG)，这会干扰亲代野生型病毒的复制。为了检验它们的治疗潜力，我们通过删除脊髓灰质炎病毒的衣壳编码区创建了一个 DVG。引人注目的是，腹膜内或鼻内给予我们称为 eTIP1 的该基因组可引发抗病毒反应，抑制复制，并保护小鼠免受多种 RNA 病毒的侵害，包括肠道病毒、流感病毒和 SARS-CoV-2。虽然鼻内给药后 eTIP1 的复制仅限于鼻腔，但其抗病毒作用非细胞自主地延伸至肺部。eTIP1 广谱抗病毒作用由局部和远端 I 型干扰素反应介导。重要的是，虽然单次 eTIP1 剂量可以保护动物免受 SARS-CoV-2 感染，它还能刺激 SARS-CoV-2 中和抗体的产生，从而提供持久的保护，防止 SARS-CoV-2 再感染。因此，eTIP1 是一种安全有效的广谱抗病毒药物，可在动物模型中产生针对 SARS-CoV-2 和其他呼吸道感染的短期和长期保护作用。